This project seeks to define determinants of CNS demyelination in experimental herpes simplex virus type 2 (HSV-2) infection, and to refine and test a hypothesis which relates HSV-2 infection to the human demyelinative disease, mltiple sclerosis (MS). Our previous studies suggest that major features of HSV-2 epidemiology and pathology are consistent with a hypothesis that HSV-2 is etiologic in MS. During FY 1984, studies published or in press have provided evidence which further defines the spectrum of experimental CNS disease produced by HSV-2. These studies provide insights into human disease which this agent is known to cause, and suggest how it could produce MS. Specifically, they show for the first time that: 1) Virus is occasionally found in axons in acute demyelinative lesions, which may explain the distinctive tract-associated topography of some demyelinative lesions we have previously described in experimental HSV-2 infection. These lesions are similar to those which have been described in MS. 2) When infected by a natural genital route, some mice develop an acute, nonfatal demyelinative disease of the CNS, while others develop other clinically recognized neurological syndromes, including non-fatal meningitis and fatal panmyelitis. Other mice have no detectable CNS lesions. In man, similar mechanisms could produce non-fatal CNS demyelinative disease in genital HSV-2 infection.